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Prostate cancer is characterized by heterogeneity in the clinical course that often does not correlate with morphologic features of the tumor. Metastasis reflects the most adverse outcome of prostate cancer, and to date there are no reliable morphologic features or serum biomarkers that can reliably predict which patients are at higher risk of deve...
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... analysis revealed that metastatic prostate cancer exhibits altered regulation of amino acid, carbohy- drate and nucleotide metabolism consistent with the pro- liferative capacity and altered energy needs of metastatic tumors (data not shown). In the context of prostate cancer biology, genes involved in cell-adhesion, bone remode- ling, cell-cycle and transcription are of particular interest ( Table 4). Disruption of cell adhesion and altered interac- tion with the extracellular matrix is a hallmark of meta- static tumors [3]. ...
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Citations
... GILT is overexpressed in PCa and is associated with a poor prognosis To investigate the underlying mechanisms of PCa, we employed microarray analysis on five pairs of fresh PCa samples. To gain further insight into the malignant progression of PCa, we incorporated published data on PCa metastasis (GSE6752) [23], androgen resistance (GSE101607) [24], and the TCGA_GTEx-PRAD dataset. By cross-analyzing genes that were significantly overexpressed across the four datasets (fold change ≥1.5, p < 0.05), we identified 106 genes that showed consistent overexpression. ...
... Additionally, we incorporated two datasets from the Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/): one consisting of 10 primary PCa samples and 20 metastatic PCa samples (GSE6752) [23], and another comprising 8 untreated PCa samples and 40 CRPC samples (GSE101607) [24]. ...
Gamma-interferon-induced lysosomal thiol reductase (GILT), known for catalyzing disulfide bond reduction, is involved in various physiological processes. While the involvement of GILT in the development of various tumors has been demonstrated, the mechanisms underlying its regulation in prostate cancer (PCa) are not fully understood. In the present study, we confirmed that GILT was significantly upregulated in PCa and facilitated tumor metastasis. Mechanistically, GILT stabilized the cofilin protein by competitively binding to cofilin with Src family tyrosine kinase (SRC), inhibiting SRC-mediated tyrosine phosphorylation of cofilin, thereby suppressing the ubiquitination pathway degradation of cofilin. GILT overexpression stabilized and increased the protein level of cofilin in PCa cells and promoted the metastasis of PCa cells by accelerating actin dynamics through cofilin-mediated actin severing. Our findings reveal a novel mechanism of GILT in PCa and provide a new potential target for the diagnosis and treatment of PCa patients.
... These 11 candidates advanced because they positively associated with prostate cancer biochemical recurrence and worse disease-free survival outcomes in at least one dataset with P-values of <0.01, or because their positive correlations (P < 0.05) with biochemical recurrence and worse disease-free survival are consistent in both datasets in either biochemical recurrence or worse disease-free survival (Supplementary Fig. S1B). The expression levels (in counts) of the 11 candidates were downloaded from the Chandran UR, BMC Cancer, [19] dataset (GDS2545, GSE6919 on Gene Expression Omnibus). The samples are then grouped based on the tissue of origin, including normal prostate tissues, benign prostate tissue that is adjacent to the tumour, localised prostate cancer tumour, and prostate cancer metastasis. ...
... Then, these 11 candidates were further analysed in the Chandran UR, BMC Cancer, [19] dataset to discover candidates associated with metastasis relative to localised prostate cancer and normal samples in these datasets [17,19] ( Supplementary Fig. S1A, B). This led to the identification of 7 genes that fit these criteria (U2AF2, RUVBL1, HDGF, FABP4, XPO1, POSTN, and STMN1) (Fig. 1c, d). ...
... Then, these 11 candidates were further analysed in the Chandran UR, BMC Cancer, [19] dataset to discover candidates associated with metastasis relative to localised prostate cancer and normal samples in these datasets [17,19] ( Supplementary Fig. S1A, B). This led to the identification of 7 genes that fit these criteria (U2AF2, RUVBL1, HDGF, FABP4, XPO1, POSTN, and STMN1) (Fig. 1c, d). ...
Background
Despite nearly 100% 5-year survival for localised prostate cancer, the survival rate for metastatic prostate cancer significantly declines to 32%. Thus, it is crucial to identify molecular indicators that reflect the progression from localised disease to metastatic prostate cancer.
Methods
To search for molecular indicators associated with prostate cancer metastasis, we performed proteomic analysis of rapid autopsy tissue samples from metastatic prostate cancer ( N = 8) and localised prostate cancer ( N = 2). Then, we utilised multiple independent, publicly available prostate cancer patient datasets to select candidates that also correlate with worse prostate cancer clinical prognosis.
Results
We identified 154 proteins with increased expressions in metastases relative to localised prostate cancer through proteomic analysis. From the subset of these candidates that correlate with prostate cancer recurrence ( N = 28) and shorter disease-free survival ( N = 37), we identified a 5-gene signature panel with improved performance in predicting worse clinical prognosis relative to individual candidates.
Conclusions
Our study presents a new 5-gene signature panel that is associated with worse clinical prognosis and is elevated in prostate cancer metastasis on both protein and mRNA levels. Our 5-gene signature panel represents a potential modality for the prediction of prostate cancer progression towards the onset of metastasis.
... The following comparisons were made: The GSE3325 [29], GSE3933 [30], and GSE68882 [31] datasets were compared between metastatic and primary prostate cancer groups. The GSE32269 [32], GSE6811 [33], GSE70770 [34], GSE6752 [35], and GSE35988 [36] datasets were compared between mCRPC and prostate cancer groups. The GSE101607 dataset was used to compare AR-driven and non-AR-driven groups. ...
The rise of treatment resistance and variability across malignant profiles has made precision oncology an imperative in today’s medical landscape. Prostate cancer is a prevalent form of cancer in males, characterized by significant diversity in both genomic and clinical characteristics. The tumor microenvironment consists of stroma, tumor cells, and various immune cells. The stromal components and tumor cells engage in mutual communication and facilitate the development of a low-oxygen and pro-cancer milieu by producing cytokines and activating pro-inflammatory signaling pathways.
In order to discover new genes associated with tumor cells that interact and facilitate a hypoxic environment in prostate cancer, we conducted a cutting-edge bioinformatics investigation. This included analyzing high-throughput genomic datasets obtained from the cancer genome atlas (TCGA).
A combination of weighted gene co-expression network analysis and single-cell sequencing has identified nine dysregulated immune hub genes (AMACR, KCNN3, MME, EGFR, FLT1, GDF15, KDR, IGF1, and KRT7) that are believed to have significant involvement in the biological pathways involved with the advancement of prostate cancer enviriment. In the prostate cancer environment, we observed the overexpression of GDF15 and KRT7 genes, as well as the downregulation of other genes. Additionally, the cBioPortal platform was used to investigate the frequency of alterations in the genes and their effects on the survival of the patients. The Kaplan-Meier survival analysis indicated that the changes in the candidate genes were associated with a reduction in the overall survival of the patients.
In summary, the findings indicate that studying the genes and their genomic changes may be used to develop precise treatments for prostate cancer. This approach involves early detection and targeted therapy.
... The GEO was used to access genomics data available for prostate cancer (GSE6919) (Yu et al, 2004;Chandran et al, 2007) and breast cancer (GSE14017 and GSE14018) (Zhang et al, 2009) cohorts. Log 2transformed gene expression data of CALCRL, RAMP1, RAMP2, and RAMP3 from patient samples were compared between primary prostate cancer (n = 65) and metastatic prostate cancer (n = 25) obtained from GSE6919; between breast cancer with brain metastasis (n = 15), lung metastasis (n = 4), and bone metastasis (n = 10) obtained from GSE14017; and between breast cancer with brain metastasis (n = 7), lung metastasis (n = 16), liver metastasis (n = 5), and bone metastasis (n = 8) obtained from GSE14017 using GraphPad Prism 9 software (GraphPad Software Inc.). ...
Although the role of peripheral nerves in cancer progression has been appreciated, little is known regarding cancer/sensory nerve crosstalk and its contribution to bone metastasis and associated pain. In this study, we revealed that the cancer/sensory nerve crosstalk plays a crucial role in bone metastatic progression. We found that (i) periosteal sensory nerves expressing calcitonin gene–related peptide (CGRP) are enriched in mice with bone metastasis; (ii) cancer patients with bone metastasis have elevated CGRP serum levels; (iii) bone metastatic patient tumor samples express elevated calcitonin receptor-like receptor (CRLR, a CGRP receptor component); (iv) higher CRLR levels in cancer patients are negatively correlated with recurrence-free survival; (v) CGRP induces cancer cell proliferation through the CRLR/p38/HSP27 pathway; and (vi) blocking sensory neuron–derived CGRP reduces cancer cell proliferation in vitro and bone metastatic progression in vivo. This suggests that CGRP-expressing sensory nerves are involved in bone metastatic progression and that the CGRP/CRLR axis may serve as a potential therapeutic target for bone metastasis.
... nlm.nih.gov/geo/), including GSE48403, GSE51873, GSE126881, GSE78201, GSE44905, GSE64143, GSE8511, GSE6752, GSE6919, GSE23451, GSE29079, GSE70769, GSE46602, and GSE141551 [22][23][24][25][26][27][28][29][30][31][32]. ChIP-seq data of AR in PCa cells was downloaded from GEO database as GSM2058879, GSM1501185 and GSM1586660, respectively [33,34]. ...
Although targeting the androgen signaling pathway by androgen receptor (AR) inhibitors, including enzalutamide, has shown therapeutic effectiveness, inevitable emergence of acquired resistance remains a critical challenge in the treatment of advanced prostate cancer (PCa). Recognizing targetable genomic aberrations that trigger endocrine treatment failure holds great promise for advancing therapeutic interventions. Here, we characterized PLXNA1, amplified in a subset of PCa patients, as a contributor to enzalutamide resistance (ENZR). Elevated PLXNA1 expression facilitated PCa proliferation under enzalutamide treatment due to AKT signaling activation. Mechanistically, PLXNA1 recruited NRP1 forming a PLXNA1-NRP1 complex, which in turn potentiated the phosphorylation of the AKT. Either inhibiting PLXNA1-NRP1 complex with an NRP1 inhibitor, EG01377, or targeting PLXNA1-mediated ENZR with AKT inhibitors, abolished the pro-resistance phenotype of PLXNA1. Taken together, combination of AKT inhibitor and AR inhibitors presents a promising therapeutic strategy for PCa, especially in advanced PCa patients exhibiting PLXNA1 overexpression.
... Comparison of PLOD2 RNA expression between localized prostate tumor samples (n = 65), and metastatic castrate-resistant prostate cancer (mCRPC) samples (n = 25) derived from metastatic sites of 4 patients, was conducted using a dataset accessed from the Gene Expression Omnibus (GEO) under the accession number GEO: GSE6919. RNA was extracted and gene expression was analyzed as previously described [31]. The Student's t test was used to assess statistical significance. ...
Background
Metastatic relapse of prostate cancer after radiotherapy is a significant cause of prostate cancer-related morbidity and mortality. PLOD2 is a mediator of invasion and metastasis that we identified as being upregulated in our highly aggressive radiorecurrent prostate cancer cell line.
Methods
Patient dataset analysis was conducted using a variety of prostate cancer cohorts. Prostate cancer cell lines were treated with siRNA, or the drug PX-478 prior to in vitro invasion, migration, or in vivo chick embryo (CAM) extravasation assay. Protein levels were detected by western blot. For RNA analysis, RNA sequencing was conducted on PLOD2 knockdown cells and validated by qRT-PCR.
Results
PLOD2 is a negative prognostic factor associated with biochemical relapse, driving invasion, migration, and extravasation in radiorecurrent prostate cancer. Mechanistically, HIF1α upregulation drives PLOD2 expression in our radiorecurrent prostate cancer cells, which is effectively inhibited by HIF1α inhibitor PX-478 to reduce invasion, migration, and extravasation. Finally, the long non-coding RNA LNCSRLR acts as a promoter of invasion downstream of PLOD2.
Conclusions
Together, our results demonstrate for the first time the role of PLOD2 in radiorecurrent prostate cancer invasiveness, and point towards its potential as a therapeutic target to reduce metastasis and improve survival outcomes in prostate cancer patients.
... Understanding the molecular events involved in the development of metastatic PCa has the potential to identify biological determinants that can aid in prognosis and development of more effective therapies [17]. Differentially expressed genes (DEGs) analysis in PCa offers valuable insights by identifying genes with altered expression levels, highlighting potential key players in the disease, though with some inherent limitations. ...
... The gene expression dataset of PCa generated and published by Chandran et al. [17] were used for this study. The dataset served as the basis for the analysis and exploration conducted in this study. ...
Prostate cancer (PCa) is a complex and biologically diverse disease with no curative treatment options at present. This study aims to utilize computational methods to explore potential anti-PCa compounds based on differentially expressed genes (DEGs), with the goal of identifying novel therapeutic indications or repurposing existing drugs. The methods employed in this study include DEGs-to-drug prediction, pharmacokinetics prediction, target prediction, network analysis, and molecular docking. The findings revealed a total of 79 upregulated DEGs and 110 downregulated DEGs in PCa, which were used to identify drug compounds capable of reversing the dysregulated conditions (dexverapamil, emetine, parthenolide, dobutamine, terfenadine, pimozide, mefloquine, ellipticine, and trifluoperazine) at a threshold probability of 20% on several molecular targets, such as serotonin receptors 2a/2b/2c, HERG protein, adrenergic receptors alpha-1a/2a, dopamine D3 receptor, inducible nitric oxide synthase (iNOS), epidermal growth factor receptor erbB1 (EGFR), tyrosine-protein kinases, and C-C chemokine receptor type 5 (CCR5). Molecular docking analysis revealed that terfenadine binding to inducible nitric oxide synthase (-7.833 kcal.mol⁻¹) and pimozide binding to HERG (-7.636 kcal.mol⁻¹). Overall, binding energy ΔGbind (Total) at 0 ns was lower than that of 100 ns for both the Terfenadine-iNOS complex (-101.707 to -103.302 kcal.mol⁻¹) and Ellipticine-TOPIIα complex (-42.229 to -58.780 kcal.mol⁻¹). In conclusion, this study provides insight on molecular targets that could possibly contribute to the molecular mechanisms underlying PCa. Further preclinical and clinical studies are required to validate the therapeutic effectiveness of these identified drugs in PCa disease.
... Additionally, exosomal HOXD-AS1 enhances osteolytic loss and tumor metastasis in the microenvironment via the miR-361-5p/FOXM1 axis [143]. FOXM1 is involved in a metastasis-related gene network, including those related to cellular adhesion and bone microenvironment [146]. ...
Prostate cancer (PCa) has the highest frequency of diagnosis among solid tumors and ranks second as the primary cause of cancer-related deaths. Non-coding RNAs (ncRNAs), such as microRNAs, long non-coding RNAs and circular RNAs, frequently exhibit dysregulation and substantially impact the biological behavior of PCa. Compared with circulating ncRNAs, ncRNAs loaded into exosomes are more stable because of protection by the lipid bilayer. Furthermore, exosomal ncRNAs facilitate the intercellular transfer of molecules and information. Increasing evidence suggests that exosomal ncRNAs hold promising potential in the progression, diagnosis and prognosis of PCa. This review aims to discuss the functions of exosomal ncRNAs in PCa, evaluate their possible applications as clinical biomarkers and therapeutic targets, and provide a comprehensive overview of the ncRNAs regulatory network in PCa. We also identified ncRNAs that can be utilized as biomarkers for diagnosis, staging, grading and prognosis assessment in PCa. This review offers researchers a fresh perspective on the functions of exosomal ncRNAs in PCa and provides additional options for its diagnosis, progression monitoring, and prognostic prediction.
... High expression of FOXM1 in glioblastoma correlates with the tumorigenicity of the glioma cells [36]. In prostate cancer, FOXM1 overexpression is also highly correlated with metastasis [37]. Importantly, FOXM1 is reported to be required for survival, quiescence and self-renewal of LSCs in vivo via April 26, 2024 Volume 16 Issue 4 ...
BACKGROUND
Leukemia stem cells (LSCs) are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia (AML), as they are protected by the bone marrow microenvironment (BMM) against conventional therapies. Gossypol acetic acid (GAA), which is extracted from the seeds of cotton plants, exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.
AIM
To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.
METHODS
In this study, LSCs were magnetically sorted from AML cell lines and the CD34+CD38- population was obtained. The expression of leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) and forkhead box M1 (FOXM1) was evaluated in LSCs, and the effects of GAA on malignancies and mitochondrial function were measured.
RESULTS
LRPPRC was found to be upregulated, and GAA inhibited cell proliferation by degrading LRPPRC. GAA induced LRPPRC degradation and inhibited the activation of interleukin 6 (IL-6)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 3 signaling, enhancing chemosensitivity in LSCs against conventional chemotherapies, including L-Asparaginase, Dexamethasone, and cytarabine. GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC. Furthermore, GAA induced reactive oxygen species accumulation, disturbed mitochondrial homeostasis, and caused mitochondrial dysfunction. By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC, GAA resulted in the elimination of LSCs. Meanwhile, GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.
CONCLUSION
Taken together, the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.
... Studies have shown that ANO7 mRNA expression decreases from low-grade to highgrade cancer [13,14] and that ANO7 is downregulated in metastatic PrCa [15,16]. Previously, immunohistochemistry study results on the inverse relationship between protein expression and Gleason grade were inconclusive [17,18]. ...
Prostate cancer affects millions of men globally. The prostate cancer-associated gene ANO7 is downregulated in advanced prostate cancer, whereas benign tissue and low-grade cancer display varying expression levels. In this study, we assess the spatial correlation between ANO7 mRNA and protein using fluorescent in situ hybridization and immunohistochemistry for the detection of mRNA and protein in parallel sections of tissue microarrays prepared from radical prostatectomy samples. We show that ANO7 mRNA and protein expression correlate in prostate tissue. Furthermore, we show that ANO7 mRNA is enriched in the nuclei of the luminal cells at 89% in benign ducts and low-grade cancer, and at 78% in high-grade cancer. The nuclear enrichment of ANO7 mRNA was validated in prostate cancer cell lines 22Rv1 and MDA PCa 2b using droplet digital polymerase chain reaction (ddPCR) on RNA isolated from nuclear and cytoplasmic fractions of the cells. The nuclear enrichment of ANO7 mRNA was compared to the nuclearly-enriched lncRNA MALAT1, confirming the surprisingly high nuclear retention of ANO7 mRNA. ANO7 has been suggested to be used as a diagnostic marker and a target for immunotherapy, but a full comprehension of its role in prostate cancer progression is currently lacking. Our results contribute to a better understanding of the dynamics of ANO7 expression in prostatic tissue.
